Nanoparticle delivery of <i>CD40</i> siRNA suppresses alloimmune responses by inhibiting activation and differentiation of DCs and macrophages.

Abstract

<i>CD40</i> is an important costimulatory molecule expressed on antigen-presenting cells (APCs) and plays a critical role for APC activation, offering a promising therapeutic target for preventing allograft rejection. Here, we developed a biodegradable nanoparticle small interfering RNA delivery system (si<i>CD40</i>/NPs) to effectively deliver <i>CD40</i> siRNA (si<i>CD40</i>) into hematopoietic stem cells (HSCs), myeloid progenitors, and mature dendritic cells (DCs) and macrophages. Injection of si<i>CD40</i>/NPs not only down-regulated <i>CD40</i> expression in DCs and macrophages but also inhibited the differentiation of HSCs and/or myeloid progenitors into functional DCs and macrophages. Furthermore, si<i>CD40</i>/NPs treatment significantly prolonged allograft survival in mouse models of skin allotransplantation. In addition to reiteration of the role of <i>CD40</i> in APC activation, our findings highlight a previously unappreciated role of <i>CD40</i> in DC and macrophage differentiation from their progenitors. Furthermore, our results support the effectiveness of si<i>CD40</i>/NPs in suppressing alloimmune responses, providing a potential means of facilitating tolerance induction and preventing allotransplant rejection.